University of Massachusetts Medical School Faculty Publications

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RNA Therapeutics Institute; Department of Biochemistry and Molecular Pharmacology; Department of Neurology; Graduate School of Biomedical Sciences

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Article Preprint


Amino Acids, Peptides, and Proteins | Biochemistry | Molecular Biology | Nervous System Diseases | Structural Biology


Toxic dipeptide repeat (DPR) proteins are produced from expanded G4C2 hexanucleotide repeats in the C9ORF72 gene, which cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two DPR proteins, poly-PR and poly-GR, repress cellular translation but the molecular mechanism remains unknown. Here we show that poly-PR and poly-GR of ≥ 20 repeats inhibit the ribosome’s peptidyl-transferase activity at nanomolar concentrations, comparable to specific translation inhibitors. High-resolution cryo-EM structures reveal that poly-PR and poly-GR block the polypeptide tunnel of the ribosome, extending into the peptidyl-transferase center. Consistent with these findings, the macrolide erythromycin, which binds in the tunnel, competes with the DPR proteins and restores peptidyl-transferase activity. Our results demonstrate that strong and specific binding of poly-PR and poly-GR in the ribosomal tunnel blocks translation, revealing the structural basis of their toxicity in C9ORF72-ALS/FTD.


Biochemistry, ribosomes, Toxic dipeptide repeat (DPR) proteins, C9ORF72 gene, C9ORF72 gene, amyotrophic lateral sclerosis, ALS, frontotemporal dementia, FTD

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bioRxiv 2020.08.30.274597; doi: Link to preprint on bioRxiv.


This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.

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Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.